This project is a series of controlled clinical trials evaluating the analgesic efficacy and safety of novel therapeutic agents and strategies for the control of chronic orofacial pain. Specific objectives of this project are: 1) to evaluate the analgesic potential of investigational analgesics acting through peripheral and central mechanisms; and 2) to develop novel investigational strategies for optimizing evaluating therapeutic efficacy in ambulatory patients with chronic orofacial pain, and 3.) to evaluate the role of inter-individual variation in the development of chronic pain and the response to analgesic drugs. All clinical trials are double-blinded with random allocation of treatments to parallel groups and multiple dependent measures of analgesic efficacy, side effect liability, and neuroendocrine responses. Subjects are evaluated prior to enrollment by a multidisciplinary team to rule out possible undiagnosed medical problems, e.g. fibromyalgia, and confirm suitability based on prospective inclusion and exclusion criteria. Following participation in a study, they are provided a summary of findings and therapeutic recommendations are made to their referring physician/dentist for continued treatment. Comparison of a selective COX-2 inhibitor to dual COX-1/COX-2 NSAIDs: A current protocol evaluated the therapeutic efficacy and side effect liability of a selective inhibitor of cyclooxygenase (COX) - 2 inhibitor in comparison to a dual acting non-steroidal anti-inflammatory drug (NSAID) and a placebo. Subjects with early onset of TMD (< three months) are initially evaluated for inclusion based on prospective inclusion/exclusion criteria and then randomly allocated to a six-week course of one of the three treatments. Daily pain diaries using standard analgesic scales will estimate analgesic efficacy; patient self-report will elicit side effects. Statistical comparison is made between treatments with both parametric and non-parametric methods to determine if the selective COX-2 inhibitor has analgesic efficacy comparable or superior to ibuprofen for this indication. Naproxen significantly reduced the symptoms of painful temporomandibular joint disc displacement with reduction as determined by most efficacy measures. Significant improvement in pain intensity occurred within 3 weeks of treatment and was sustained throughout the 6-week study. Clinically significant improvement in mandibular range of motion was observed for naproxen compared to celecoxib and placebo. Celecoxib showed slightly better pain reduction than placebo, but not significantly effective for temporomandibular disorder pain. Celecoxib and naproxen were well tolerated with similar number of reported adverse effects. Dual COX-1/COX-2 inhibition with naproxen was demonstrated to be effective for the treatment of painful TMD as seen by significant improvement in clinical signs and symptoms compared to celecoxib and placebo, suggesting that inhibition of both COX isozymes is needed to achieve effective analgesia for this type of pain. Future course of studies: The evaluation of patients with failed TMJ implants illustrates the need for prospective studies to evaluate novel and standard therapies for TMDs in order to provide patients and clinicians with objective data on efficacy and side effect liability. The need to carefully characterize subjects for these investigations, include placebo and standard treatment groups to assess assay sensitivity, and evaluate the treatments over an adequate time course provide substantial barriers to conducting such studies at one site. Efforts over the next year will be directed at developing and validating methods for conducting collaborative, multi-site clinical trials needed to objectively evaluate novel pharmacologic and non-pharmacolgic treatments for TMD.